Hydroisoquinoline derivatives

Abstract

##STR1## Compounds of formula (I) in which, R is linear or branched alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl or furan-2-yl alkyl; R 1 and R 2 , which may be the same or different, are each hydrogen, hydroxy, alkoxy, or halogen; R 3 is hydrogen, hydroxy or alkoxy; "Het" is optionally substituted single or fused heteroxyclic ring, containing from 5 to 10 ring atoms and comprising up to four heteratoms in the or each ring, selected from oxygen, nitrogen and sulphur; R 4 and R 5 , which may be the same or different, are each hydrogen alkyl, halogen, nitro; CF, cyano, alkoxy carbonyl, NH, alkylcarbonylamino, hydroxy, alkoxy, or benzyl, are selective delta receptor agonists and are useful in the treatment of pain.

We claim: 
     
       1. A compound, or solvate or salt thereof, of formula (I): ##STR11## in which, R is linear or branched C 1-5  alkyl, C 3-7  cycloalkyl, C 4-6  cycloalkylalkyl, C 3-5  alkenyl, aryl, aralkyl or furan-2-yl alkyl; R 1  and R 2 , which may be the same or different, are each hydrogen, hydroxy, C 1-3  alkoxy, or halogen;   R 3  is hydrogen, hydroxy or C 1-3  alkoxy; "Het" is indolo, N-methylindolo. N-ethylindolo, N-benzylindolo, benzofuro, benzothieno, quino or quinoxalino;   R 4  and R 5 , which may be the same or different, are each hydrogen, C 1-3  alkyl, halogen, nitro,   
     
     
       2. A compound according to claim 1, in which R is methyl, ethyl, cyclopropylmethyl, propyl, or 2-phenylethyl. 
     
     
       3. A compound according to claim 1, in which each of R 1  & R 2  is hydrogen, hydroxy or methoxy. 
     
     
       4. A compound according to claim 1 in which each of R 4  & R 5  is hydrogen, methyl, ethyl, fluorine, chlorine, hydroxy, methoxy or benzyl. 
     
     
       5. A compound selected from: 2-ethyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydroindolo[2,3-g]isoquinoline;   2-methyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aα-octahydroindolo[2,3-g]isoquinoline;   2-ethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydroindolo[2,3-g]isoquinoline;   4aα-(3-methoxyphenyl)-2-methyl- 1,2,3,4,4a,5,11,11aα-octahydroindolo[2,3-g]isoquinoline;   2-methyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4 a,5,11,11aβ-octahydroindolo [2,3-g]isoquinoline;   2-methyl-4a{x-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydroindolo [2,3-g]isoquinoline;   2,6-dimethyl-4a{x-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydroindolo[2,3-g]isoquinoline;   2,6-dimethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydroindolo[2,3-g]isoquinoline;   2-methyl-4aα-phenyl- 1,2,3,4,4a,5,11,11aβ-octahydroindolo[2,3-g]isoquinoline;   2-methyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydrobenzofuro[2,3-g]isoquinoline;   2-methyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydrobenzofuro[2,3-g]isoquinoline;   2,9-dimethyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydroindolo[2,3-g]isoquinoline;   
     
     
       2. 9-dimethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydroindolo[2,3-g]isoquinoline; 2-methyl-4aα-(3-hydroxyphenyl)-9-fluoro- 1,2,3,4,4a,5,11,11aβ-octahydroindolo[2,3-g]isoquinoline;   2-methyl-4aα-(3-methoxyphenyl)-9-fluoro- 1,2,3,4,5,11,11aβ-octahydroindolo[2,3-g]isoquinoline;   2-methyl-4aα-(3-hydroxyphenyl)-7-chloro- 1,2,3,4,5,11,11aβ-octahydroindolo[2,3-g]isoquinoline;   2-meth yl-4aα-(3-methoxyphenyl)-7-chloro-1,2,3,4,4a,5,11,11aβ-octahydroindolo[2,3-g]isoquinoline;   2-methyl-4aα-(3-hydroxyphenyl)-9-chloro-1,2,3,4,4a,5,11,11aβ-octahydroindolo[2,3-g]isoquinoline;   2-methyl-4aα-(3-methoxyphenyl)-9-chloro- 1,2,3,4,4a,5,11,11aβ-octahydroindolo[2,3-g]isoquinoline;   2-ethyl-6-methyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydroindolo[2,3-g]isoquinoline;   2-ethyl-6-methyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydroindolo[2,3-g]isoquinoline;   2-methyl-4aα-phenyl-9-methoxy-1,2,3,4,4a,5,11,11aβ-octahydroindolo[2,3-g]isoquinoline;   2-methyl-4aα-phenyl-9-hydroxy-1,2,3,4,4a,5,11,11aβ-octahydroindolo[2,3-g]isoquinoline;   2-methyl-4aα-(2-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydroindolo[2,3-g]isoquinoline;   2-methyl-4aα-(2-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydroindolo[2,3-g]isoquinoline;   2-methyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,12,12aβ-octahydroquino[2,3-g]isoquinoline;   2-methyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aβ-octahydroquino[2,3-g]isoquinoline;   2-(2-phenylethyl)-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydroindolo[2,3-g]isoquinoline;   2-(2-phenylethyl)-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydroindolo[2,3-g]isoquinoline;   2-ethyl-4aα-(3-methoxyphenyl)-6-benzyl-1,2,3,4,4a,5,11,11aβ-octahydroindolo[2,3-g]isoquinoline;   2-ethyl-4aα-(3-hydroxyphenyl)-6-benzyl-1,2,3,4,4a,5,11,11aβ-octahydroindolo[2,3-g]isoquinoline;   2,6-diethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydroindolo[2,3-g]isoquinoline;   2,6-diethyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydroindolo[2,3-g]isoquinoline;   2-n-propyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydroindolo[2,3-g]isoquinoline;   2-n-propyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydroindolo[2,3-g]isoquinoline;   2-cyclopropylmethyl-4aα-(3-methoxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydroindolo[2,3-g]isoquinoline;   2-cyclopropylmethyl-4au-(3-hydroxyphenyl)-1,2,3,4,4a,5,11,11aβ-octahydroindolo[2,3-g]isoquinoline;   
     
     
       6. A pharmaceutical composition comprising a compound according to any one of claim 1 and a pharmaceutically acceptable carrier. 
     
     
       7. A method for the treatment and/or prophylaxis of pain in mammals, which comprises administering to the mammal in need of such treatment and/or prophylaxis an effective amount of a compound according to claim 1. 
     
     
       8. A compound according to claim 2 wherein each of R 1  and R 2  is hydrogen, hydroxy or methoxy. 
     
     
       9. A compound according to claim 2 wherein each of R 4  and R 5  is hydrogen, methyl, ethyl, fluorine, chlorine, hydroxy, methoxy or benzyl. 
     
     
       10. A compound according to claim 2 wherein each of R 1  and R 2  is hydrogen, hydroxy or methoxy; Het is indolo, N-methylindolo, N-ethylindolo, N-benzylindolo, benzofuro, benzothieno, quino or quinoxaline; and each of R 4  and R 5  is hydrogen, methyl, ethyl, fluorine, chlorine, hydroxy, methoxy or benzyl. 
     
     
       11. A pharmaceutical composition comprising a compound according to claim 5 and a pharmaceutically acceptable carrier. 
     
     
       12. A method for the treatment or prophylaxis of pain in mammals, which comprises administering to a mammal in need thereof an effective amount of a compound according to claim 5.